Summary

Autophagy is a mechanism by which parts of a cell that are old and unneeded are segregated inside structures called "autophagosomes". The materials ingested by this autophagy are brought to cellular compartments called "lysosomes," which are specific intracellular compartments for degradation, and the degraded products are re-used for cell metabolism. We have shown that, in mice, deficiency in lysosomal proteinases such as cathepsin D or cathepsins B and L induces the accumulation of lysosomes containing ceroid-lipofuscin; the phenotypes of these mice resemble those of neuronal ceroid lipofuscinosis (NCL). In these mutant mice, the accumulation of abnormal lysosomal structures appears in accordance with an increase in the amount of membrane-bound microtubule associated protein 1 light chain 3 (LC3), a marker of "autophagosomes" in neurons. Such autophagosomes often contain granular osmiophilic deposits, a hallmark of NCL, together with part of the cytoplasm, which contains undigested materials. These data strongly argue for a major involvement of autophagy in the pathogenesis of NCL, although it remains largely unknown what signaling is essential for autophagosome formation.

Neonatal hypoxic/ischemic (H/I) brain injury causes neurological impairment, including cognitive and motor dysfunction, as well as seizures. However, the molecular mechanisms regulating neuron death after H/I injury are poorly defined and remain controversial. Here we show that Atg7, a gene essential for autophagy induction, is a critical mediator of H/I-induced neuron death. Neonatal mice subjected to H/I injury show dramatically increased autophagosome formation and extensive hippocampal neuron death that is regulated by both caspase-3-dependent and -independent execution. Mice deficient in Atg7 show nearly complete protection from both H/I-induced caspase-3 activation and neuron death, indicating that Atg7 is critically positioned upstream of multiple

'Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

2Division of Gross Anatomy and Morphogenesis, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan neuronal death executioner pathways. Adult H/I brain injury also produces a significant increase in autophagy, but, unlike neonatal H/I, neuron death is almost exclusively caspase-3-independent. These data suggest that autophagy plays an essential role in triggering neuronal death execution after H/I injury.

Although it has been considered that autophagy is essential for the maintenance of cellular metabolism, our data suggest that excess autophagy under pathological conditions may lead to cell death.

Key words Autophagy ■ Lysosomes ■ Cathepsins ■ LC3 ■ Brain ischemia

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